Brigatinib Monotherapy in Children with R/R ALK+ ALCL, IMT, or Other Solid Tumors: Updated Results from the Brigaped (ITCC-098) Phase 1 Dose-Escalation Study

Introduction Brigatinib is an orally administered second-generation anaplastic lymphoma kinase (ALK) inhibitor (ALKi) with good central nervous system penetration, approved for the treatment of ALK-positive (ALK+) non-small cell lung cancer in adults. The recommended dose in adults is 180 mg once daily (QD) after a 7-day lead-in at 90 mg QD. This report describes updated results of the phase 1 part of the BrigaPED trial (NCT04925609). This study is part of a Pediatric Investigation Plan, sponsored by the Princess Máxima Center and supported by Takeda Pharmaceuticals International Co. Methods The BrigaPED trial is a multicenter, non-randomized open label phase 1-2 study of brigatinib in pediatric and young adult patients. Patients aged ≥1 to <18 years and a body weight > 10 kg with relapsed or refractory ALK+ malignancies, including ALCL and inflammatory myofibroblastic tumors (IMT), were eligible for enrollment in the phase 1 part of this study. ALK positivity on immunohistochemistry was sufficient to enroll ALCL patients. Frontline ALK+ ALCL patients who were minimal residual disease (MRD) positive after one course of chemotherapy met the definition of refractory disease. Patients with IMT were also eligible in frontline in case of unresectable or metastatic disease. Previous treatment with other ALKi was allowed. Written informed consent and adequate organ function were required for study eligibility. In phase 1, brigatinib was dose escalated using the rolling-six design. The starting dose was allometrically scaled based on the adult approved dose, with one dose escalation, and a lower dose-level (DL) in case of dose-limiting toxicities (DLT). Brigatinib was administered once daily as tablets in 28-day cycles. DLTs were evaluated during the 7-day lead-in and the first cycle, to determine the recommended phase 2 dose (RP2D). Patients were assessed for safety, pharmacokinetics, activity, and efficacy. Response in ALCL was evaluated according to international pediatric non-Hodgkin lymphoma (IPNHL) response criteria and by response evaluation criteria for solid tumors (RECIST) for solid tumors. Qualitative MRD was assessed in ALCL patients using Reverse Transcriptase-PCR and digital PCR. Results Ten patients were enrolled between 08-2022 and 08-2023, 9 ALCL (3 frontline MRD+ and 6 relapsed), and 1 sarcoma NOS with an ALK fusion. Median age at inclusion was 9 years (range: 6-17 years). All patients were pretreated with chemotherapy and 3 with another ALKi. At database cut-off (21 June 2024), patients had received a median of 18 cycles (range 10-23 cycles). No DLT was observed on DL1 (n=4), and 1 on DL2 (n=6, grade (G)3 neutropenia > 7 days). Following dose reduction, this patient could resume brigatinib successfully. Common treatment-related adverse events (AE) were (n any G; n ≥ G3): asymptomatic CPK increase (8;2), nausea/vomiting (7;0), abdominal pain (6;0), and AST/ALT elevation (4;0). Reported AEs of special interest included ophthalmological events (3;0) and weight gain (3;2). No brigatinib related pulmonary toxicity or endocrine AEs were observed. Steady-state PK exposure on DL2 was within the predefined target range. Amongst 9 ALCL patients, 7 were MRD positive at screening and 8 had evaluable disease on imaging. The objective response rate (ORR) was 100%, with all ALCL patients achieving CR (n=6/8) or CRu (n=2/8), and a PR in the sarcoma patient. MRD negativity was obtained in 6/7 patients after a median of 1 cycle (range: 1-16 cycles). All ALCL patients were still on treatment with an ongoing response for a median duration of 18 months (range: 9-21 months). Conclusions Brigatinib monotherapy is well tolerated and demonstrated promising preliminary signs of activity in pediatric ALK+ ALCL, with no signs of cumulative toxicity. All ALCL patients are still on treatment. The RP2D was established at DL2, corresponding to 150 mg QD in patients 18-40 kg, or 240 mg QD in patients > 40 kg, which is higher than the adult approved dose. The phase 2 part of this study is currently open for accrual with disease-specific cohorts for ALK+ ALCL and IMT (age ≥1 - <26 years). An age-appropriate formulation is in development and will be used to confirm the RP2D in smaller children.